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SUMMARY1. Lactating rats were implanted with a cannula in a lateral cerebral ventricle to deliver morphine (up to 50 jtg/h) chronically from a subcutaneous osmotically driven mini-pump. After infusion of morphine for 5 days the rats were anaesthetized with urethane and prepared with ventral surgery for recording the electrical activity of single, antidromically identified neurones in the supraoptic nucleus.2. A single i.v. injection of naloxone (5 mg/kg) in these rats provoked a longlasting, large increase in intramammary pressure, but in control rats had negligible effects. Concentrations in plasma of oxytocin, measured by radioimmunoassay in samples of femoral arterial blood, rose from 44-7 + 2-5 to 1072 1 + 89-5 pg/ml (means+s.E.M.) 6 min after naloxone in the morphine-treated rats. In control rats, the concentration of oxytocin in plasma rose only from 42-1 + 2-9 to 125-1 + 28-2 pg/ml after naloxone.3. Naloxone produced a transient increase in arterial blood pressure in morphinetreated but not control rats. Concentrations in plasma of vasopressin, measured by radioimmunoassay in samples of femoral arterial blood, rose in morphine-treated rats from 7-4 + 2-4 to 29-2 + 3-7 pg/ml after naloxone, but did not rise significantly in control rats.4. Naloxone (1-5 mg/kg) produced a prompt and prolonged increase in the discharge rate of each of ten continuously active (putative oxytocin) cells recorded from ten morphine-treated rats. The discharge rate of the six cells tested at the highest dose (5 mg/kg) increased by an average of 6-3 Hz (360 %) within 5 min, and the firing rate remained elevated for at least 30 min; the discharge rate of six continuously active supraoptic neurones recorded in control rats was not affected by naloxone.5. The firing activity of five phasic (putative vasopressin) supraoptic neurones in morphine-treated rats was increased for at least 30 min by the injection of naloxone; these increases were the result of a raised intraburst firing rate with no change in burst duration or frequency. One phasic neurone was inhibited for 15 min, and one phasic neurone was unaffected. R. J. BICKNELL AND OTHERS 6. The excitatory effects of naloxone on neurones in the supraoptic nucleus of morphine-treated rats were not explained by changes in blood pressure or osmolarity and did not depend on suckling or a cholinergic pathway.7. The concentrations of oxytocin in plasma and the operation of the milk-ejection reflex were similar in the controls and morphine-treated rats, prior to naloxone. These findings indicate tolerance to initial inhibitory effects of morphine on oxytocin secretion. Likewise, before naloxone the concentrations of vasopressin in plasma and firing activity of phasic neurones were similar in the morphine-treated and control groups, indicating tolerance to any effects of morphine on vasopressin neurones.8. The uniform excitation of continuous neurones, accompanied by massive secretion of oxytocin provoked by naloxone in the morphine-treated rats, indicates dependence on morphine in the centra...

Neurohypophysial hormone release, and the electrical activity of single neurons of the supraoptic nucleus, were monitored in urethane-anaesthetized rats. Immediately after electrolytic lesions of the region anterior and ventral to the third ventricle (AV3V region), supraoptic neurons showed little spontaneous activity and their responses to ip injection of hypertonic saline were severely impaired; corresponding deficits were found in the secretion of both oxytocin and vasopressin. Similar deficits in oxytocin secretion were also found in rats following electrolytic lesions which destroyed all or part of the subfornical organ; however the effects of the lesions were not additive: rats with lesions of both the AV3V region and the subfornical organ region showed a similar degree of impairment of osmotically stimulated oxytocin secretion to rats with lesions of either site alone. Such deficits might occur either as a result of destruction of osmoresponsive projections to the magnocellular nuclei, or as a result of destruction of an afferent input which is essential for the full expression of the innate osmosensitivity of supraoptic neurons. To test the latter possibility, supraoptic neurons in AV3V-lesioned rats were activated by continuous application of glutamate, and then tested with ip injection of hypertonic saline. Five of seven cells tested responded significantly to the hyperosmotic stimulus, though the responses were significantly weaker than observed in sham-lesioned rats. We suggest that the innate osmosensitivity of supraoptic neurons does contribute to their responses to systemic osmotic stimulation, but that expression of this innate osmosensitivity requires inputs frorr.$he AV3V region and/or the subfornical organ, some of which may also be osmoresponsive. Electrical stimulus pulses applied to the AV3V region influenced the electrical activity of most supraoptic neurons strongly: the predominant response was a short-latency, short-duration inhibition followed by long-latency, long-duration excitation. Whereas intracerebroventricuiar administration of the angiotensin I 1 antagonist saralasin reduced spontaneous or osmotically induced activity of supraoptic neurons, the neuronal responses to AV3V stimulation were impaired only with relatively high doses of saralasin. We conclude that angiotensin Il-sensitive neurons are an important component of the afferent pathways that sustain the excitability of supraoptic neurons, but that angiotensin is probably not the major transmitter of the projection from the AV3V region to the supraoptic nucleus.The region anterior and ventral to the third ventricle (AV3V region), which includes the median preoptic nucleus and parts of the lamina terminalis, including the organum vasculosum of the lamina terminalis (OVLT), plays an essential role in water balance and electrolyte homeostasis in mammals. Lesions of this region severely impair the osmoregulation of vasopressin release and of drinking, and lead to a persistent hypernatraemia, the aetiology of which remai...

We asked whether the relationship between oxygen delivery and oxygen consumption is different between patients who have sepsis and normal (n = 6) or increased (n = 8) concentrations of plasma lactate. We determined oxygen consumption using analysis of respiratory gases while increasing oxygen delivery using a dobutamine infusion. The relationship between oxygen delivery and consumption was y = 124 + 0.043 * x in the normal lactate group and y = 131 - 0.003 * x in the high lactate group (95% CI for differences in slopes, -0.003 to 0.096; p < or = 0.05 for slope, normal versus high lactate). In the normal lactate group, direct oxygen consumption increased by only 8 +/- 6 ml/min/m2 after dobutamine infusion (from 144 +/- 26 to 153 +/- 22 ml/min/m2, p < or = 0.02) despite an average increase of 220 +/- 80 ml/min/m2 in oxygen delivery (from 446 +/- 91 to 666 +/- 90 ml/min/m2, p < or = 0.01). The oxygen extraction ratio fell from 0.27 +/- 0.03 to 0.21 +/- 0.02 after dobutamine (p < or = 0.017). In the high lactate group, direct oxygen consumption decreased by 1 +/- 6 ml/min/m2 after dobutamine (from 131 +/- 33 to 130 +/- 35 ml/min/m2, p > 0.60) despite an average increase of 168 +/- 138 ml/min/m2 in oxygen delivery (from 467 +/- 194 to 635 +/- 300 ml/min/m2, p < or = 0.01). The oxygen extraction ratio fell from 0.30 +/- 0.14 to 0.26 +/- 0.12 after dobutamine (p < or = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

At the neurosecretory terminals in the neural lobe, oxytocin secretion is restrained by co‐secreted endogenous opioids, which act via kappa‐receptors. The co‐secreted opioids include products of pro‐dynorphin (released by both vasopressin and oxytocin terminals) and proenkephalin (released by oxytocin terminals). In morphine‐tolerant rats this opioid mechanism is more effective, but in late pregnancy it is less effective. Opioids also act directly on oxytocin cell bodies, via separate mu‐ and kappa‐receptors, inhibiting excitation by all stimuli tested, and also exert presynaptic and more distal actions on afferent systems. During chronic morphine exposure, tolerance and dependence develop in oxytocin neurones; the former involves reduction in mu‐opioid receptor density, while the latter may involve compensatory upregulation of mechanisms regulating Ca2+ influx. In mid‐pregnancy, the effectiveness of opioid mechanisms in the neural lobe increases, assisting the accumulation of oxytocin stores in advance of parturition, but by the end of pregnancy the effectiveness of these mechanisms is reduced. At this time, a separate endogenous opioid system, acting via mu‐receptors, actively restrains the electrical activity of oxytocin neurones. Release of this endogenous opioid inhibition may contribute to the increase in activity during parturition analogous to that occurring during morphine withdrawal excitation. Central opioid mechanisms retain the ability to control oxytocin neurones during parturition, and can interrupt established parturition by inhibiting oxytocin neurone firing rate in disadvantageous environmental circumstances.